DESCRIPTION

FluMist Quadrivalent (Influenza Vaccine Live, Intranasal)
is a live quadrivalent vaccine for administration by intranasal spray. FluMist
Quadrivalent contains four vaccine virus strains: an A/H1N1 strain, an A/H3N2
strain and two B strains. FluMist Quadrivalent contains B strains from both the
B/Yamagata/16/88 and the B/Victoria/2/87 lineages. FluMist Quadrivalent is
manufactured according to the same process as FluMist.

The influenza virus strains in FluMist Quadrivalent are
(a) cold-adapted (ca) (i.e., they replicate efficiently at 25°C, a temperature
that is restrictive for replication of many wild-type influenza viruses); (b) temperature-sensitive
(ts) (i.e., they are restricted in replication at 37°C (Type B strains) or 39°C
(Type A strains), temperatures at which many wild-type influenza viruses grow
efficiently); and (c) attenuated (att) (i.e., they do not produce classic
influenza-like illness in the ferret model of human influenza infection).

No evidence of reversion has been observed in the
recovered vaccine strains that have been tested (135 of possible 250 recovered
isolates) using FluMist [seeCLINICAL PHARMACOLOGY]. For each of the
four reassortant strains in FluMist Quadrivalent, the six internal gene
segments responsible for ca, ts, and att phenotypes are derived from a master
donor virus (MDV), and the two segments that encode the two surface
glycoproteins, hemagglutinin (HA) and neuraminidase (NA), are derived from the
corresponding antigenically relevant wild-type influenza viruses. Thus, the
four viruses contained in FluMist Quadrivalent maintain the replication
characteristics and phenotypic properties of the MDV and express the HA and NA
of wild-type viruses. For the Type A MDV, at least five geneYeah. It hatic loci in three
different internal gene segments contribute to the ts and att phenotypes. For the
Type B MDV, at least three genetic loci in two different internal gene segments
contribute to both the ts and att properties; five genetic loci in three gene
segments control the ca property.

Each of the reassortant strains in FluMist Quadrivalent
express the HA and NA of wild- type viruses that are related to strains
expected to circulate during the 2016-2017 influenza season. Three of the
viruses (A/H1N1, A/H3N2 and one B strain) have been recommended by the United
States Public Health Service (USPHS) for inclusion in the annual trivalent and
quadrivalent influenza vaccine formulations. An additional B strain has been
recommended by the USPHS for inclusion in the quadrivalent influenza vaccine
formulation.

Specific pathogen-free (SPF) eggs are inoculated with
each of the reassortant strains and incubated to allow vaccine virus
replication. The allantoic fluid of these eggs is harvested, pooled, and then
clarified by filtration. The virus is concentrated by ultracentrifugation and
diluted with stabilizing buffer to obtain the final sucrose and potassium
phosphate concentrations. The viral harvests are then sterile filtered to
produce the monovalent bulks. Each lot is tested for ca, ts, and att phenotypes
and is also tested extensively by in vitro and in vivo methods to detect
adventitious agents. Monovalent bulks from the four strains are subsequently
blended and diluted as required to attain the desired potency with stabilizing
buffers to produce the quadrivalent bulk vaccine. The bulk vaccine is then
filled directly into individual sprayers for nasal administration.

The tip attached to the sprayer is equipped with a nozzle
that produces a fine mist that is primarily deposited in the nose and
nasopharynx. FluMist Quadrivalent is a colorless to pale yellow suspension and
is clear to slightly cloudy.

Indications & Dosage

INDICATIONS

FluMist® Quadrivalent is a vaccine indicated for active
immunization for the prevention of influenza disease caused by influenza A
subtype viruses and type B viruses contained in the vaccine [seeDESCRIPTION].

FluMist Quadrivalent is approved for use in persons 2
through 49 years of age.

DOSAGE AND ADMINISTRATION

FOR INTRANASAL ADMINISTRATION BY A HEALTHCARE
PROVIDER.

Dosing Information

Administer FluMist Quadrivalent according to the
following schedule:

Age

Dose

Schedule

2 years through 8 years

1 or 2 dosesa,

If 2 doses, administerat least 1 month apart

0.2 mLb each

9 years through 49 years

1 dose, 0.2 mLb

-

a 1 or 2 doses
depends on vaccination history as per Advisory Committee on Immunization
Practices annual recommendations on prevention and control of influenza with
vaccines. b Administer
as 0.1 mL per nostril.
“-” indicates information is not applicable

Administration Instructions

Each sprayer contains a single dose (0.2 mL) of FluMist
Quadrivalent; administer approximately one half of the contents of the
single-dose intranasal sprayer into each nostril (each sprayer contains 0.2 mL
of vaccine). Refer to Figure 1 for step-by-step administration instructions.
Following administration, dispose of the sprayer according to the
standard procedures for medical waste (e.g., sharps container or biohazard
container).

Figure 1

Note: Active inhalation (i.e., sniffing) is not
required by the patient during vaccine administration.

HOW SUPPLIED

Dosage Forms And Strengths

Each 0.2 mL dose is a suspension supplied in a
single-dose pre-filled intranasal sprayer.

Storage And Handling

The cold chain [2-8°C (35-46°F)] must be maintained when
transporting FluMist Quadrivalent.

FLUMIST QUADRIVALENT SHOULD BE STORED IN A
REFRIGERATOR BETWEEN 2-8°C (35-46°F) UPON RECEIPT. THE PRODUCT MUST BE USED
BEFORE THE EXPIRATION DATE ON THE SPRAYER LABEL.

DO NOT FREEZE.

Keep FluMist Quadrivalent sprayer in outer carton in
order to protect from light.

A single temperature excursion up to 25°C (77°F) for 12
hours has been shown to have no adverse impact on the vaccine. After a
temperature excursion, the vaccine should be returned immediately to the
recommended storage condition (2°C - 8°C) and used as soon as feasible.
Subsequent excursions are not permitted.

Once FluMist Quadrivalent has been administered or has
expired, the sprayer should be disposed of according to the standard procedures
for medical waste (e.g., sharps container or biohazard container).

SIDE EFFECTS

Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
vaccine cannot be directly compared to rates in the clinical trials of another
vaccine and may not reflect the rates observed in practice.

This safety experience with FluMist is relevant to
FluMist Quadrivalent because both vaccines are manufactured using the same
process and have overlapping compositions [see DESCRIPTION]. A total of
9537 children and adolescents 1 through 17 years of age and 3041 adults 18
through 64 years of age received FluMist in randomized, placebo-controlled
Studies D153-P501, AV006, D153-P526, AV019, and AV009 [3 used Allantoic Fluid
containing Sucrose-Phosphate-Glutamate (AF-SPG) placebo, and 2 used saline
placebo] described below. In addition, 4179 children 6 through 59 months of age
received FluMist in Study MI-CP111, a randomized, active-controlled trial.
Among pediatric FluMist recipients 6 months through 17 years of age, 50% were
female; in the study of adults, 55% were female. In MI-CP111, AV006, D153-P526,
AV019, and AV009, subjects were White (71%), Hispanic (11%), Asian (7%), Black
(6%), and Other (5%), while in D153-P501, 99% of subjects were Asian.

A total of 1382 children and adolescents 2 through 17
years of age and 1198 adults 18 through 49 years of age received FluMist
Quadrivalent in randomized, active-controlled Studies MI-CP208 and MI-CP185.
Among pediatric FluMist Quadrivalent recipients 2 through 17 years of age, 51%
were female; in the study of adults, 55% were female. In Studies MI-CP208 and
MI-CP185, subjects were White (73%), Asian (1%), Black or African-American
(19%), and Other (7%); overall, 22% were Hispanic or Latino.

FluMist In Children And Adolescents

The safety of FluMist was evaluated in an AF-SPG
placebo-controlled study (AV019) conducted in a Health Maintenance Organization
(HMO) in children 1 through 17 years of age (FluMist = 6473, placebo = 3216).
An increase in asthma events, captured by review of diagnostic codes, was
observed in children younger than 5 years of age who received FluMist compared
to those who received placebo (Relative Risk 3.53, 90% CI: 1.1, 15.7).

In Study MI-CP111, children 6 through 59 months of age
were randomized to receive FluMist or inactivated Influenza Virus Vaccine
manufactured by Sanofi Pasteur Inc. Wheezing requiring bronchodilator therapy
or accompanied by respiratory distress or hypoxia was prospectively monitored
from randomization through 42 days post last vaccination. Hospitalization due
to all causes was prospectively monitored from randomization through 180 days
post last vaccination. Increases in wheezing and hospitalization (for any
cause) were observed in children 6 months through 23 months of age who received
FluMist compared to those who received inactivated Influenza Virus Vaccine, as
shown in Table 1.

Table 1: Percentages of Children with Hospitalizations
and Wheezing from Study MI-CP111a

Adverse Reaction

Age Group

FluMist
(n/N)

Active Controlb
(n/N)

Hospitalizationsc

6-23 months

4.2%(84/1992)

3.2%(63/1975)

24-59 months

2.1%(46/2187)

2.5%(56/2198)

Wheezingd

6-23 months

5.9%(117/1992)

3.8%(75/1975)

24-59 months

2.1%(47/2187)

2.5%(56/2198)

a NCT00128167; see www.clinicaltrials.govb Inactivated Influenza Virus Vaccine manufactured by Sanofi Pasteur
Inc., administered intramuscularly. c Hospitalization due to any cause from randomization through 180
days post last vaccination.d Wheezing requiring bronchodilator therapy or accompanied by
respiratory distress or hypoxia evaluated from randomization through 42 days
post last vaccination.

Most hospitalizations observed were due to
gastrointestinal and respiratory tract infections and occurred more than 6
weeks post vaccination. In post-hoc analysis, rates of hospitalization in
children 6 through 11 months of age were 6.1% (42/684) in FluMist recipients
and 2.6% (18/683) in inactivated Influenza Virus Vaccine recipients.

Table 2 shows pooled solicited adverse reactions
occurring in at least 1% of FluMist recipients and at a higher rate ( ≥ 1%
rate difference after rounding) compared to placebo post Dose 1 for Studies
D153-P501 and AV006, and solicited adverse reactions post Dose 1 for Study
MI-CP111. Solicited adverse reactions were those about which parents/guardians
were specifically queried after receipt of FluMist, placebo, or control
vaccine. In these studies, solicited reactions were documented for 10 days post
vaccination. Solicited reactions following the second dose of FluMist were
similar to those following the first dose and were generally observed at a
lower frequency.

Table 2: Summary of Solicited Adverse Reactions
Observed Within 10 Days after Dose 1 for FluMist and Either Placebo or Active
Control Recipients in Children 2 through 6 Years of Age

In a separate saline placebo-controlled trial (D153-P526) in
a subset of older children and adolescents 9 through 17 years of age who
received one dose of FluMist, the solicited adverse reactions as well as
unsolicited adverse reactions reported were generally consistent with
observations from the trials in Table 2. Abdominal pain was reported in 12% of
FluMist recipients compared to 4% of placebo recipients and decreased activity
was reported in 6% of FluMist recipients compared to 0% of placebo recipients.

In Study AV018, in which FluMist was concomitantly
administered with Measles, Mumps, and Rubella Virus Vaccine Live (MMR,
manufactured by Merck & Co., Inc.) and Varicella Virus Vaccine Live
(manufactured by Merck & Co., Inc.) to children 12 through 15 months of
age, adverse reactions were similar to those seen in other clinical trials of
FluMist.

FluMist
Quadrivalent In Children And Adolescents

In the randomized, active-controlled Study MI-CP208 that
compared FluMist Quadrivalent and FluMist in children and adolescents 2 through
17 years of age, the rates of solicited adverse reactions reported were similar
between subjects who received FluMist Quadrivalent and FluMist. Table 3
includes solicited adverse reactions post Dose 1 from Study MI-CP208 that
either occurred at a higher rate ( ≥ 1% rate difference after rounding) in
FluMist Quadrivalent recipients compared to FluMist recipients or were
identified in previous FluMist clinical studies (see Table 2). In this study,
solicited adverse reactions were documented for 14 days post vaccination.
Solicited adverse reactions post Dose 2 were observed at a lower frequency
compared to those post Dose 1 for FluMist Quadrivalent and were similar between
subjects who received FluMist Quadrivalent and FluMist.

Table 3: Summary of Solicited Adverse Reactionsa Observed
Within 14 Days after Dose 1 for FluMist Quadrivalent and FluMist Recipients in
Study MI-CP208b in Children and Adolescents 2 through 17 Years of Age

FluMist Quadrivalent
N = 1341-1377d

FluMistc
N =901-920d

Event

%

%

Runny Nose/Nasal Congestion

32

32

Headache

13

12

Decreased Activity (Lethargy)

10

10

Sore Throat

9

10

Decreased Appetite

6

7

Muscle Aches

4

5

Fever

> 100°F by any route

7

5

> 100 - ≤ 101°F by any route

3

2

> 101 - ≤ 102°F by any route

2

2

a Solicited adverse reactions that occurred at
a higher rate ( ≥ 1% rate difference after rounding) in FluMist
Quadrivalent recipients compared to FluMist recipients or were identified in
previous FluMist trials (see Table 2). b NCT01091246; see www.clinicaltrials.govc Represents pooled data from the two FluMist study arms [see Clinical
Studies].d Number of evaluable subjects for each event.

In Study MI-CP208, no unsolicited adverse reactions
occurred at a higher rate (1% or greater) in FluMist Quadrivalent recipients
compared to FluMist recipients.

FluMist Quadrivalent In Adults

In the randomized, active-controlled Study MI-CP185 that
compared FluMist Quadrivalent and FluMist in adults 18 through 49 years of age,
the rates of solicited adverse reactions reported were generally similar
between subjects who received FluMist Quadrivalent and FluMist. Table 4
presents solicited adverse reactions that either occurred at a higher rate ( ≥
1% rate difference after rounding) in FluMist Quadrivalent recipients compared
to FluMist recipients or were identified in Study AV009.

Table 4: Summary of Solicited Adverse Reactionsa Observed
Within 14 Days after Dose 1 for FluMist Quadrivalent and FluMist Recipients in
Study MI-CP185b in Adults 18 through 49 Years of Age

FluMist Quadrivalent
N = 1197d

FluMistc
N = 597d

Event

%

%

Runny Nose/Nasal Congestion

44

40

Headache

28

27

Sore Throat

19

20

Decreased Activity (Lethargy)

18

18

Cough

14

13

Muscle Aches

10

10

Decreased Appetite

6

5

a Solicited adverse reactions that occurred at
a higher rate ( ≥ 1% rate difference after rounding) in FluMist
Quadrivalent recipients compared to FluMist recipients or were identified in
Study AV009. b NCT00860067; see www.clinicaltrials.govc Represents pooled data from the two FluMist study arms [see Clinical
Studies].d Number of evaluable subjects for each event.

In Study MI-CP185, no unsolicited adverse reactions
occurred at a higher rate (1% or greater) in FluMist Quadrivalent recipients
compared to FluMist recipients.

Postmarketing Experience

The following events have been spontaneously reported
during post approval use of FluMist. Because these events are reported voluntarily
from a population of uncertain size, it is not always possible to reliably
estimate their frequency or establish a causal relationship to vaccine
exposure.

DRUG INTERACTIONS

Aspirin Therapy

Do not administer FluMist Quadrivalent to children and
adolescents through 17 years of age who are receiving aspirin therapy or
aspirin-containing therapy because of the association of Reye's syndrome with
aspirin and wild-type influenza [see CONTRAINDICATIONS]. Avoid
aspirin-containing therapy in these age groups during the first 4 weeks after
vaccination with FluMist Quadrivalent unless clearly needed.

Antiviral Agents Against Influenza A and/or B

Antiviral drugs that are active against influenza A
and/or B viruses may reduce the effectiveness of FluMist Quadrivalent if
administered within 48 hours before, or within 2 weeks after vaccination. The
concurrent use of FluMist Quadrivalent with antiviral agents that are active
against influenza A and/or B viruses has not been evaluated. If antiviral
agents and FluMist Quadrivalent are administered concomitantly, revaccination
should be considered when appropriate.

Concomitant Administration With Inactivated Vaccines

The safety and immunogenicity of FluMist Quadrivalent
when administered concomitantly with inactivated vaccines have not been
determined. Studies of FluMist and FluMist Quadrivalent excluded subjects who
received any inactivated or subunit vaccine within two weeks of enrollment.

Concomitant Administration With Other Live Vaccines

Concomitant administration of FluMist Quadrivalent with
Measles, Mumps, and Rubella Virus Vaccine Live (MMR, manufactured by Merck
& Co., Inc.) or the Varicella Virus Vaccine Live (manufactured by Merck
& Co., Inc.) has not been studied. Concomitant administration of FluMist
with MMR and the varicella vaccine was studied in children 12 through 15 months
of age [see Clinical Studies]. Concomitant administration of FluMist
with the MMR and the varicella vaccine in children older than 15 months of age has
not been studied.

Intranasal Products

There are no data regarding co-administration of FluMist
Quadrivalent with other intranasal preparations.

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risks Of Hospitalization And Wheezing In Children Younger
Than 24 Months Of Age

In clinical trials, risks of hospitalization and wheezing
were increased in children younger than 2 years of age who received FluMist
(trivalent Influenza Vaccine Live, Intranasal) [seeADVERSE REACTIONS].
This observation with FluMist is relevant to FluMist Quadrivalent because both
vaccines are manufactured using the same process and have overlapping
compositions [seeDESCRIPTION].

Asthma, Recurrent Wheezing, And Active Wheezing

Children younger than 5 years of age with recurrent
wheezing and persons of any age with asthma may be at increased risk of
wheezing following administration of FluMist Quadrivalent. FluMist Quadrivalent
has not been studied in persons with severe asthma or active wheezing.

Guillain-Barré Syndrome

The 1976 swine influenza vaccine (inactivated) was associated with an
elevated risk of Guillain-Barré syndrome (GBS). Evidence for
causal relation of GBS with other influenza vaccines is inconclusive; if an
excess risk exists, based on data for inactivated influenza vaccines, it is
probably slightly more than 1 additional case per 1 million persons vaccinated
[1]. If GBS has occurred within 6 weeks of any prior influenza vaccination, the
decision to give FluMist Quadrivalent should be based on careful consideration
of the potential benefits and potential risks.

Altered Immunocompetence

FluMist Quadrivalent has not been studied in
immunocompromised persons. The effectiveness of FluMist has not been studied in
immunocompromised persons. Data on safety and shedding of vaccine virus after
administration of FluMist in immunocompromised persons are limited to 173
persons with HIV infection and 10 mild to moderately immunocompromised children
and adolescents with cancer [seeCLINICAL PHARMACOLOGY].

Medical Conditions Predisposing To Influenza
Complications

The safety of FluMist Quadrivalent in individuals with
underlying medical conditions that may predispose them to complications
following wild-type influenza infection has not been established.

Management Of Acute Allergic Reactions

Appropriate medical treatment and supervision must be
available to manage possible anaphylactic reactions following administration of
the vaccine [seeCONTRAINDICATIONS].

Limitations Of Vaccine Effectiveness

FluMist Quadrivalent may not protect all individuals
receiving the vaccine.

Patient Counseling Information

Advise the vaccine recipient or caregiver to read the
FDA-approved patient labeling (Information for Patients and Their Caregivers).

Inform vaccine recipients or their parents/guardians of
the need for two doses at least 1 month apart in children 2 through 8 years of
age, depending on vaccination history. Provide the Vaccine Information
Statements (VIS) which are required by the National Childhood Vaccine Injury
Act of 1986 to be given with each immunization.

Asthma And Recurrent Wheezing

Ask the vaccinee or their parent/guardian if the vaccinee
has asthma. For children younger than 5 years of age, also ask if the vaccinee
has recurrent wheezing since this may be an asthma equivalent in this age
group. Inform the vaccinee or their parent/guardian that there may be an
increased risk of wheezing associated with FluMist Quadrivalent in persons
younger than 5 years of age with recurrent wheezing and persons of any age with
asthma [see WARNINGS AND PRECAUTIONS].

Vaccination With A Live Virus Vaccine

Inform vaccine recipients or their parents/guardians that
FluMist Quadrivalent is an attenuated live virus vaccine and has the potential
for transmission to immunocompromised household contacts.

Adverse Event Reporting

Instruct the vaccine recipient or their parent/guardian
to report adverse reactions to their healthcare provider.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

FluMist Quadrivalent has not been evaluated for its
carcinogenic or mutagenic potential or its potential to impair fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category B

A developmental and reproductive toxicity study has been
performed in female rats administered FluMist Quadrivalent either three times
(during the period of organogenesis) or six times (prior to gestation and
during the period of organogenesis), 200 microliter/rat/occasion (approximately
150 human dose equivalents), by intranasal instillation and has revealed no
evidence of impaired fertility or harm to the fetus due to FluMist
Quadrivalent. There are however, no adequate and well controlled studies in
pregnant women. Because animal studies are not always predictive of human
response FluMist Quadrivalent should be administered during pregnancy only if
clearly needed.

Nursing Mothers

It is not known whether FluMist Quadrivalent is excreted
in human milk. Because some viruses are excreted in human milk, caution should
be exercised when FluMist Quadrivalent is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of FluMist Quadrivalent in
children 24 months of age and older is based on data from FluMist clinical
studies and a comparison of post-vaccination antibody titers between persons
who received FluMist Quadrivalent and those who received FluMist [see Clinical
Studies]. FluMist Quadrivalent is not approved for use in children younger
than 24 months of age because use of FluMist in children 6 through 23 months
has been associated with increased risks of hospitalization and wheezing in clinical
trials [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Geriatric Use

FluMist Quadrivalent is not approved for use in persons
65 years of age and older because in a clinical study (AV009), effectiveness of
FluMist to prevent febrile illness was not demonstrated in adults 50 through 64
years of age [see Clinical Studies]. In this study, solicited events
among individuals 50 through 64 years of age were similar in type and frequency
to those reported in younger adults. In a clinical study of FluMist in persons
65 years of age and older, subjects with underlying high-risk medical
conditions (N = 200) were studied for safety. Compared to controls, FluMist
recipients had a higher rate of sore throat.

Overdosage & Contraindications

OVERDOSE

No information provided.

CONTRAINDICATIONS

Severe Allergic Reactions

Do not administer FluMist Quadrivalent to persons who
have had a severe allergic reaction (e.g., anaphylaxis) to any component of the
vaccine [seeDESCRIPTION] including egg protein, or after a previous
dose of any influenza vaccine.

Concomitant Aspirin Therapy And Reye's Syndrome In Children
And Adolescents

Do not administer FluMist Quadrivalent to children and
adolescents through 17 years of age who are receiving aspirin therapy or
aspirin-containing therapy because of the association of Reye's syndrome with
aspirin and wild-type influenza infection [seeDRUG INTERACTIONS].

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

Immune mechanisms conferring protection against influenza
following receipt of FluMist Quadrivalent vaccine are not fully understood;
serum antibodies, mucosal antibodies, and influenza-specific T cells may play a
role.

FluMist and FluMist Quadrivalent contain live attenuated
influenza viruses that must infect and replicate in cells lining the
nasopharynx of the recipient to induce immunity. Vaccine viruses capable of
infection and replication can be cultured from nasal secretions obtained from
vaccine recipients (shedding) [see Pharmacodynamics].

Pharmacodynamics

Shedding Studies

Shedding of vaccine viruses within 28 days of vaccination
with FluMist was evaluated in (1) multi-center study MI-CP129 which enrolled
healthy individuals 6 through 59 months of age (N = 200); and (2) multi-center
study FM026 which enrolled healthy individuals 5 through 49 years of age (N =
344). In each study, nasal secretions were obtained daily for the first 7 days
and every other day through either Day 25 and on Day 28 or through Day 28. In
study MI-CP129, individuals with a positive shedding sample at Day 25 or Day 28
were to have additional shedding samples collected every 7 days until culture
negative on 2 consecutive samples. Results of these studies are presented in
Table 5.

Table 5: Characterization of Shedding with FluMist in
Specified Age Groups by Frequency, Amount, and Duration (Study MI-CP129a
and Study FM026b)

Age

Number of Subjects

Sheddingc

Peak Titer (TCID50/mL)d

Shedding After Day 11

Day of Last Positive Culture

6-23 monthse

99

89

< 5 log10

7.0

Day 23f

24-59 months

100

69

< 5 log10

1.0

Day 25g

5-8 years

102

50

< 5 log10

2.9

Day 23h

9-17 years

126

29

< 4 log10

1.6

Day 28h

18-49 years

115

20

< 3 log10

0.9

Day 17h

a NCT00344305; see www.clinicaltrials.govb NCT00192140; see www.clinicaltrials.govc Proportion of subjects with detectable virus at any time point
during the 28 days.d Peak titer at any time point during the 28 days among samples
positive for a single vaccine virus.e FluMist and FluMist Quadrivalent are not approved for use in
children younger than 24 months of age [seeADVERSE REACTIONS].f A single subject who shed previously on Days 1-3; TCID50/mL was
less than 1.5 log10 on Day 23.g A single subject who did not shed previously; TCID50/mL was less
than 1.5 log10.h A single subject who did not shed previously; TCID50/mL was less
than 1.0 log10.

The highest proportion of subjects in each group shed one
or more vaccine strains on Days 2-3 post vaccination. After Day 11 among
individuals 2 through 49 years of age (n = 443), virus titers did not exceed
1.5 log10 TCID50/mL.

Studies In Immunocompromised Individuals

Safety and shedding of vaccine virus following FluMist
administration were evaluated in 28 HIV-infected adults [median CD4 cell count
of 541 cells/mm³] and 27 HIV-negative adults 18 through 58 years of age. No
serious adverse events were reported during the one-month follow-up period.
Vaccine strain (type B) virus was detected in 1 of 28 HIV-infected subjects on
Day 5 only, and in none of the HIV-negative FluMist recipients.

Safety and shedding of vaccine virus following FluMist
administration were also evaluated in children in a randomized (1:1),
cross-over, double-blind, AF-SPG placebo-controlled trial in 24 HIV-infected
children [median CD4 cell count of 1013 cells/mm³] and 25 HIV-negative children
1 through 7 years of age, and in a randomized (1:1), open-label, inactivated
influenza vaccine-controlled trial in 243HIV-infected children and adolescents
5 through 17 years of age receiving stable anti-retroviral therapy. Frequency
and duration of vaccine virus shedding in HIV-infected individuals were
comparable to that seen in healthy individuals. No adverse effects on HIV viral
load or CD4 counts were identified following FluMist administration. In the 5
through 17 year old age group, one inactivated influenza vaccine recipient and
one FluMist recipient experienced pneumonia within 28 days of vaccination (days
17 and 13, respectively). The effectiveness of FluMist and FluMist Quadrivalent
in preventing influenza illness in HIV-infected individuals has not been
evaluated.

Twenty mild to moderately immunocompromised children and
adolescents 5 through 17 years of age (receiving chemotherapy and/or radiation
therapy or who had received chemotherapy in the 12 weeks prior to enrollment)
were randomized 1:1 to receive FluMist or AF-SPG placebo. Frequency and
duration of vaccine virus shedding in these immunocompromised children and
adolescents were comparable to that seen in healthy children and adolescents.
The effectiveness of FluMist and FluMist Quadrivalent in preventing influenza
illness in immunocompromised individuals has not been evaluated.

Transmission Study

A prospective, randomized, double-blind, placebo-controlled
trial was performed in a daycare setting in children younger than 3 years of
age to assess the transmission of vaccine viruses from a vaccinated individual
to a non-vaccinated individual. A total of 197 children 8 through 36 months of
age were randomized to receive one dose of FluMist (N = 98) or AF-SPG placebo
(N = 99). Virus shedding was evaluated for 21 days by culture of nasal swab
specimens. Wild-type A (A/H3N2) influenza virus was documented to have
circulated in the community and in the study population during the trial,
whereas Type A (A/H1N1) and Type B strains did not.

At least one vaccine strain was isolated from 80% of
FluMist recipients; strains were recovered from 1-21 days post vaccination
(mean duration of 7.6 days ± 3.4 days). The cold-adapted (ca) and
temperature-sensitive (ts) phenotypes were preserved in 135 tested of 250
strains isolated at the local laboratory. Ten influenza isolates (9 influenza
A, 1 influenza B) were cultured from a total of seven placebo subjects. One
placebo subject had mild symptomatic Type B virus infection confirmed as a
transmitted vaccine virus by a FluMist recipient in the same playgroup. This
Type B isolate retained the ca, ts, and att phenotypes of the vaccine strain
and had the same genetic sequence when compared to a Type B virus cultured from
a vaccine recipient within the same playgroup. Four of the influenza Type A
isolates were confirmed as wild-type A/Panama (H3N2). The remaining isolates
could not be further characterized.

Assuming a single transmission event (isolation of the
Type B vaccine strain), the probability of a young child acquiring vaccine
virus following close contact with a single FluMist vaccinee in this daycare
setting was 0.58% (95% CI: 0, 1.7) based on the Reed-Frost model. With documented
transmission of one Type B in one placebo subject and possible transmission of
Type A viruses in four placebo subjects, the probability of acquiring a
transmitted vaccine virus was estimated to be 2.4% (95% CI: 0.13, 4.6) using
the Reed-Frost model.

Pharmacokinetics

Biodistribution

A biodistribution study of intranasally administered
radiolabeled placebo was conducted in 7 healthy adult volunteers. The mean
percentages of the delivered doses detected were as follows: nasal cavity
89.7%, stomach 2.6%, brain 2.4%, and lung 0.4%. The clinical significance of
these findings is unknown.

Clinical Studies

The effectiveness of FluMist Quadrivalent is based on
data demonstrating the clinical efficacy of FluMist in children and the
effectiveness of FluMist in adults, and a comparison of post vaccination
geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies
between individuals receiving FluMist and FluMist Quadrivalent. The clinical
experience with FluMist is relevant to FluMist Quadrivalent because both
vaccines are manufactured using the same process and have overlapping
compositions [see DESCRIPTION].

Efficacy Studies Of FluMist In Children And Adolescents

A multinational, randomized, double-blind,
active-controlled trial (MI-CP111) was performed to assess the efficacy of
FluMist compared to an intramuscularly administered, inactivated Influenza
Virus Vaccine manufactured by Sanofi Pasteur Inc. (active control) in children
6 months to less than 5 years of age during the 2004-2005 influenza season. A
total number of 3916 children without severe asthma, without use of
bronchodilator or steroids, and without wheezing within the prior 6 weeks were
randomized to FluMist and 3936 were randomized to active control. Children who
previously received any influenza vaccine received a single dose of study
vaccine, while those who never previously received an influenza vaccination (or
had an unknown history of influenza vaccination) received two doses.
Participants were then followed through the influenza season to identify illness
caused by influenza virus. As the primary endpoint, culture-confirmed modified
CDC-ILI (CDC-defined influenza-like illness) was defined as a positive culture
for a wild-type influenza virus associated within ±7 days of modified CDC-ILI.
Modified CDC-ILI was defined as fever (temperature ≥ 100°F oral or
equivalent) with cough, sore throat, or runny nose/nasal congestion on the same
or consecutive days.

In the primary efficacy analysis, FluMist demonstrated a
44.5% (95% CI: 22.4, 60.6) reduction in influenza rate compared to active
control as measured by culture-confirmed modified CDC-ILI caused by wild-type
strains antigenically similar to those contained in the vaccine. See Table 6
for a description of the results by strain and antigenic similarity.

A randomized, double-blind, saline placebo-controlled
trial (D153-P501) was performed to evaluate the efficacy of FluMist in children
12 through 35 months of age without high-risk medical conditions against
culture-confirmed influenza illness. This study was performed in Asia over two
successive seasons (2000-2001 and 2001-2002). The primary endpoint of the trial
was the prevention of culture-confirmed influenza illness due to antigenically
matched wild-type influenza. Respiratory illness that prompted an influenza
culture was defined as at least one of the following: fever ( ≥ 100.4°F
rectal or ≥ 99.5°F axillary), wheezing, shortness of breath, pulmonary
congestion, pneumonia, or otitis media; or two of the following: runny nose/nasal
congestion, sore throat, cough, muscle aches, chills, headache, irritability,
decreased activity, or vomiting. A total of 3174 children were randomized 3:2
(vaccine: placebo) to receive 2 doses of study vaccine or placebo at least 28
days apart in Year 1. See Table 7 for a description of the results.

During the second year of Study D153-P501, for children who
received two doses in Year 1 and one dose in Year 2, FluMist demonstrated 84.3%
(95% CI: 70.1, 92.4) efficacy against culture-confirmed influenza illness due
to antigenically matched wild-type influenza.

Study AV006 was a second multi-center, randomized,
double-blind, AF-SPG placebo-controlled trial performed in U.S. children
without high-risk medical conditions to evaluate the efficacy of FluMist
against culture-confirmed influenza over two successive seasons (1996-1997 and
1997-1998). The primary endpoint of the trial was the prevention of
culture-confirmed influenza illness due to antigenically matched wild-type
influenza in children who received two doses of vaccine in the first year and a
single revaccination dose in the second year. Respiratory illness that prompted
an influenza culture was defined as at least one of the following: fever ( ≥
101°F rectal or oral; or ≥ 100.4°F axillary), wheezing, shortness of
breath, pulmonary congestion, pneumonia, or otitis media; or two of the
following: runny nose/nasal congestion, sore throat, cough, muscle aches,
chills, headache, irritability, decreased activity, or vomiting. During the
first year of the study, 1602 children 15 through 71 months of age were
randomized 2:1 (vaccine: placebo). See Table 7 for a description of the
results.

a D153-P501 and AV006 data are for subjects
who received two doses of study vaccine.b In children 12 through 35 months of agec In children 15 through 71 months of aged NCT00192244; see www.clinicaltrials.gove NCT00192179; see www.clinicaltrials.govf Number and percent of subjects in per-protocol efficacy analysis
population with culture-confirmed influenza illness.g Number of subjects in per-protocol efficacy analysis population of
each treatment group of each study for the “any strain” analysis.h For D153-P501, influenza circulated through 12 months following
vaccination.i Estimate includes A/H1N1 and A/H1N2 strains. Both were considered
antigenically similar to the vaccine.

During the second year of Study AV006, children remained
in the same treatment group as in Year 1and received a single dose of FluMist
or placebo. During the second year, the primary circulating strain was the
A/Sydney/05/97 H3N2 strain, which was antigenically dissimilar from the H3N2
strain represented in the vaccine, A/Wuhan/359/95; FluMist demonstrated 87.0%
(95% CI: 77.0, 92.6) efficacy against culture-confirmed influenza illness.

Immune Response Study Of FluMist Quadrivalent In Children
And Adolescents

A multicenter, randomized, double-blind,
active-controlled, non-inferiority study (MI-CP208) was performed to assess the
immunogenicity of FluMist Quadrivalent compared to FluMist (active control) in
children and adolescents 2 through 17 years of age. A total of 2312 subjects
were randomized by site at a 3:1:1 ratio to receive either FluMist Quadrivalent
or one of two formulations of comparator vaccine FluMist, each containing a B
strain that corresponded to one of the two B strains in FluMist Quadrivalent (a
B strain of the Yamagata lineage or a B strain of the Victoria lineage).

Children 2 through 8 years of age received 2 doses of
vaccine approximately 30 days apart; children 9 years of age and older received
1 dose. For children 2 through 8 years of age with a history of influenza
vaccination, immunogenicity assessments were performed prior to vaccination and
at 28 days after the first dose. For children 2 through 8 years of age without
a history of influenza vaccination, immunogenicity assessments were performed
prior to vaccination and 28 days after the second dose. For children 9 years of
age and older, immunogenicity assessments were performed prior to vaccination
and at 28 days post vaccination.

Immunogenicity was evaluated by comparing the 4
strain-specific serum hemagglutination inhibition (HAI) antibody geometric mean
titers (GMTs) post dosing and provided evidence that the addition of the second
B strain did not result in immune interference to other strains included in the
vaccine.

Effectiveness Study Of FluMist In Adults

AV009 was a U.S. multi-center, randomized, double-blind,
AF-SPG placebo-controlled trial to evaluate effectiveness of FluMist in adults
18 through 64 years of age without high-risk medical conditions over the
1997-1998 influenza season. Participants were randomized 2:1 (vaccine:
placebo). Cultures for influenza virus were not obtained from subjects in the
trial, thus efficacy against culture-confirmed influenza was not assessed. The
A/Wuhan/359/95 (H3N2) strain, which was contained in FluMist, was antigenically
distinct from the predominant circulating strain of influenza virus during the
trial period, A/Sydney/05/97 (H3N2). Type A/Wuhan (H3N2) and Type B strains
also circulated in the U.S. during the study period. The primary endpoint of
the trial was the reduction in the proportion of participants with one or more
episodes of any febrile illness, and prospective secondary endpoints were
severe febrile illness and febrile upper respiratory illness. Effectiveness for
any of the three endpoints was not demonstrated in a subgroup of adults 50
through 64 years of age. Primary and secondary effectiveness endpoints from the
age group 18 through 49 years are presented in Table 8. Effectiveness was not
demonstrated for the primary endpoint in adults 18 through 49 years of age.

Table 8: Effectiveness of FluMist to Prevent Febrile
Illness in Adults 18 through 49 Years of Age During the 7-Week Site-Specific
Outbreak Period (Study AV009)

Endpoint

FluMist
N = 2411a n (%)

Placebo
N = 1226a n (%)

Percent Reduction

(95% CI)

Participants with one or more events of:b

Primary Endpoint:

Any febrile illness

331 (13.73)

189 (15.42)

10.9

(-5.1, 24.4)

Secondary Endpoints:

Severe febrile illness

250 (10.37)

158 (12.89)

19.5

(3.0, 33.2)

Febrile upper respiratory illness

213 (8.83)

142 (1 1.58)

23.7

(6.7, 37.5)

a Number of evaluable subjects (92.7% and
93.0% of FluMist and placebo recipients, respectively).b The predominantly circulating virus during the trial period was
A/Sydney/05/97 (H3N2), an antigenic variant not included in the vaccine.

Effectiveness was shown in a post-hoc analysis using an
endpoint of CDC-ILI in the age group 18 through 49 years of age.

Immune Response Study Of FluMist Quadrivalent In Adults

A multicenter, randomized, double-blind,
active-controlled, and non-inferiority study (MI-CP185) was performed to assess
the safety and immunogenicity of FluMist Quadrivalent compared to those of
FluMist (active control) in adults 18 through 49 years of age. A total of 1800
subjects were randomized by site at a 4:1:1 ratio to receive either 1 dose of
FluMist Quadrivalent or 1 dose of one of two formulations of comparator
vaccine, FluMist, each containing a B strain that corresponded to one of the
two B strains in FluMist Quadrivalent (a B strain of the Yamagata lineage and a
B strain of the Victoria lineage).

Immunogenicity in study MI-CP185 was evaluated by
comparing the 4 strain-specific serum hemagglutination inhibition (HAI)
antibody geometric mean titers (GMTs) post dosing and provided evidence that
the addition of the second B strain did not result in immune interference to
other strains included in the vaccine.

Concomitantly Administered Live Virus Vaccines

In Study AV018, concomitant administration of FluMist,
MMR (manufactured by Merck & Co., Inc.) and Varicella Virus Vaccine Live
(manufactured by Merck & Co., Inc.) was studied in 1245 subjects 12 through
15 months of age. Subjects were randomized in a 1:1:1 ratio to MMR, Varicella
vaccine and AF-SPG placebo (group 1); MMR, Varicella vaccine and FluMist (group
2); or FluMist alone (group 3). Immune responses to MMR and Varicella vaccines
were evaluated 6 weeks post-vaccination while the immune responses to FluMist
were evaluated 4 weeks after the second dose. No evidence of interference with
immune response to measles, mumps, rubella, varicella and FluMist vaccines was
observed.

PATIENT INFORMATION

Please read this Patient Information carefully before you or
your child is vaccinated with FluMist Quadrivalent.

This is a summary of information about FluMist Quadrivalent.
It does not take the place of talking with your healthcare provider about
influenza vaccination. If you have questions or would like more information,
please talk with your healthcare provider.

What is FluMist Quadrivalent?

FluMist Quadrivalent is a vaccine that is sprayed into the
nose to help protect against influenza. It can be used in children,
adolescents, and adults ages 2 through 49. FluMist Quadrivalent is similar to
MedImmune's trivalent Influenza Vaccine Live, Intranasal (FluMist) except
FluMist Quadrivalent provides protection against an additional influenza
strain. FluMist Quadrivalent may not prevent influenza in everyone who gets
vaccinated.

Who should not get FluMist Quadrivalent?

You should not get FluMist Quadrivalent if you:

have a severe allergy to eggs or to any inactive ingredient
in the vaccine (see “What are the ingredients in FluMist Quadrivalent?”)

have ever had a life-threatening reaction to influenza
vaccinations

are 2 through 17 years old and take aspirin or medicines
containing aspirin. Children or adolescents should not be given aspirin for 4
weeks after getting FluMist or FluMist Quadrivalent unless your healthcare
provider tells you otherwise.

Please talk to your healthcare provider if you are not sure
if the items listed above apply to you or your child.

Children under 2 years old have an increased risk of wheezing
(difficulty with breathing) after getting FluMist Quadrivalent.

Who may not be able to get FluMist
Quadrivalent?

Tell your healthcare provider if you or your child:

are currently wheezing

have a history of wheezing if under 5 years old

have had Guillain-Barré syndrome

have a weakened immune system or live with someone who has a
severely weakened immune system

If you or your child cannot take FluMist Quadrivalent, you
may still be able to get an influenza shot. Talk to your healthcare provider
about this.

How is FluMist Quadrivalent given?

FluMist Quadrivalent is a liquid that is sprayed into the
nose.

You can breathe normally while getting FluMist Quadrivalent.
There is no need to inhale or “sniff” it.

People 9 years of age and older need one dose of FluMist
Quadrivalent each year.

Children 2 through 8 years old may need 2 doses of FluMist
Quadrivalent, depending on their history of previous influenza vaccination.
Your healthcare provider will decide if your child needs to come back for a
second dose.

FluMist Quadrivalent is stored in a refrigerator (not the
freezer) between 35-46 degrees F (2-8 degrees C) upon receipt. FluMist
Quadrivalent sprayer must be kept in the carton until use in order to protect
from light. FluMist Quadrivalent must be used before the expiration date on the
sprayer label.

If you would like more information, talk to your healthcare
provider or visit www.flumistquadrivalent.com or call 1-877-633-4411.